VARIABLE DISPOSITION KINETICS AND ELECTROCARDIOGRAPHIC EFFECTS OF FLECAINIDE DURING REPEATED DOSING IN HUMANS - CONTRIBUTION OF GENETIC-FACTORS, DOSE-DEPENDENT CLEARANCE, AND INTERACTION WITH AMIODARONE

We studied the influence of cytochrome P450 2D6 (CYP2D6) on the steady -state disposition kinetics and the electrocardiographic effects of fl ecainide at two doses and during combination with amiodarone. Seven ex tensive and five poor metabolizers of dextromethorphan were studied du ring a three-period crossover study. All subjects received 50 mg fleca inide every 12 hours, alone or together with 200 mg amiodarone every 1 2 hours, and 100 mg flecainide every 12 hours for 5 days. Mean steady- state plasma concentration of flecainide and QRS change from predrug v alue did not differ significantly among extensive and poor metabolizer subjects during each study period. Except for a shortened elimination half-life and nonlinear kinetics in extensive metabolizer subjects, p henotype had no significant influence on flecainide pharmacokinetics. Combination with amiodarone resulted in an increase in mean flecainide plasma concentration and effect in subjects with both phenotypes. Our findings indicate that CYP2D6 phenotype predicts flecainide nonlinear kinetics and flecainide half-life but has no influence on electrocard iographic effects during repeated administration of flecainide or on t he extent of the amiodarone-flecainide interaction.